RET activation controlled by MAB21L4-CacyBP interaction drives squamous cell carcinoma

Epithelial squamous cell carcinomas (SCC) most commonly originate in the skin, where they display disruptions in the normally tightly regulated homeostatic balance between keratinocyte proliferation and terminal differentiation. We performed a transcriptome- wide screen for genes of unknown function...

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Published inbioRxiv
Main Authors Srivastava, Ankit, Tommasi, Cristina, Sessions, Dane, Mah, Angela, Bencomo, Tomas, Garcia, Jasmine M, Jiang, Tiffany, Lee, Michael, Shen, Joseph Y, Lek Wei Seow, Nguyen, Audrey, Rajapakshe, Kimal, Coarfa, Cristian, Tsai, Kenneth Y, Lopez-Pajares, Vanessa, Lee, Carolyn S
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 22.01.2022
Subjects
Carcinogenesis
Genetic transformation
Keratinocytes
Organoids
Protein-tyrosine kinase receptors
Ret protein
Squamous cell carcinoma
Transcription
Transcriptomes
Transfection
Tumorigenesis
Ubiquitin
Ubiquitin-protein ligase
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Summary:Epithelial squamous cell carcinomas (SCC) most commonly originate in the skin, where they display disruptions in the normally tightly regulated homeostatic balance between keratinocyte proliferation and terminal differentiation. We performed a transcriptome- wide screen for genes of unknown function that possess inverse expression patterns in differentiating keratinocytes compared to cutaneous SCC (cSCC) and identified MAB21L4 (C2ORF54) as an enforcer of terminal differentiation that suppresses carcinogenesis. Loss of MAB21L4 in human cSCC organoids enabled malignant transformation through increased expression of the receptor tyrosine kinase rearranged during transfection (RET). In addition to transcriptional upregulation of RET, MAB21L4 deletion preempted recruitment of the CacyBP-Siah1 E3 ligase complex to RET and reduced its ubiquitylation. Both genetic disruption of RET or selective RET inhibition with BLU-667 (pralsetinib) suppressed tumorigenesis in SCC organoids and in vivo tumors while inducing concomitant differentiation. Our results suggest that targeting RET activation is a potential therapeutic strategy for treating SCC. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2022.01.19.476979